Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma (HCC) Who Have Been Treated With One Prior Therapy (METIV-HCC)

March 12, 2021 updated by: Daiichi Sankyo, Inc.

A Phase 3, Randomized, Double-Blind Study of Tivantinib (ARQ 197) in Subjects With MET Diagnostic-High Inoperable Hepatocellular Carcinoma Treated With One Prior Systemic Therapy

The purpose of this study is to determine if tivantinib (ARQ 197) is effective in treating patients with MET diagnostic-high hepatocellular carcinoma (liver cancer) who have already been treated once with another therapy.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Expression of c-Met in tumors correlates with aggressive hepatocellular carcinoma (HCC) features. Overexpression of the receptor in tumor samples or high level of blood HGF in subjects is related to higher recurrence rate after surgery for HCC, while high c-Met expression correlates with shorter survival in HCC subjects. In summary, c-Met holds an important prognostic role in the natural history of HCC. This Phase 3 study in MET Diagnostic-High inoperable HCC subjects has been designed based on the results from the randomized, controlled Phase 2 study conducted by ArQule, Inc. with tivantinib versus placebo in subjects with MET Diagnostic-High inoperable HCC who have failed one prior systemic therapy, mentioned above. The purpose of this study is to confirm the efficacy of tivantinib in MET Diagnostic-High HCC subjects who were previously treated with one systemic therapy, and to further evaluate the safety profile of the experimental drug in this subject population.

Study Type

Interventional

Enrollment (Actual)

383

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Argentina
      • Pilar, Argentina
    • Buenos Aires
      • Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
    • Caba
      • Buenos Aires, Caba, Argentina
  • Australia
    • New South Wales
      • Camperdown, New South Wales, Australia
    • Victoria
      • Heidelberg, Victoria, Australia
      • Melbourne, Victoria, Australia
    • Western Australia
      • Nedlands, Western Australia, Australia
  • Austria
      • Graz, Austria
      • Innsbruck, Austria
      • Linz, Austria
      • Wien, Austria
  • Belgium
      • Brussels, Belgium
      • Ghent, Belgium
      • Leuven, Belgium
      • Liege, Belgium
  • Brazil
      • Barretos, Brazil
      • Rio de Janeiro, Brazil
    • RS
      • Porto Alegre, RS, Brazil
    • SP
      • Sao Paulo, SP, Brazil
  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada
    • Ontario
      • Toronto, Ontario, Canada
  • France
      • Amiens Cedex 1, France
      • Bordeaux Cedex, France
      • Caen Cedex 09, France
      • Clichy, France
      • Creteil, France
      • Grenoble, France
      • Lille Cedex, France
      • Marseille Cedex 09, France
      • Montpellier, France
      • Paris Cedex, France
      • Paris Cedex 12, France
      • Reims Cedex, France
      • Rennes Cedex, France
      • Toulouse Cedex 09, France
      • Villejuif Cedex, France
  • Germany
      • Aachen, Germany
      • Berlin, Germany
      • Bonn, Germany
      • Duesseldorf, Germany
      • Essen, Germany
      • Frankfurt am Main, Germany
      • Hamburg, Germany
      • Hannover, Germany
      • Heidelberg, Germany
      • Leipzig, Germany
      • Magdeburg, Germany
      • Mainz, Germany
      • Muenchen, Germany
      • Munich, Germany
      • Regensburg, Germany
      • Tuebingen, Germany
      • Ulm, Germany
      • Wuerzburg, Germany
  • Italy
      • Benevento, Italy, 82100
      • Bergamo, Italy
      • Bologna, Italy
      • Catania, Italy
      • Firenze, Italy
      • Milano, Italy
      • Modena, Italy
      • Napoli, Italy
      • Padova, Italy
      • Parma, Italy
      • Pavia, Italy
      • Pisa, Italy
      • Reggio Emilia, Italy
      • Roma, Italy
      • Turin, Italy
    • Forli-Cesena
      • Meldola, Forli-Cesena, Italy
    • Milano
      • Rozzano, Milano, Italy
    • Torino
      • Orbassano (TO), Torino, Italy
  • Netherlands
      • Amsterdam, Netherlands
  • New Zealand
      • Auckland, New Zealand
  • Portugal
      • Lisboa, Portugal
      • Porto, Portugal
      • Vila Real, Portugal
  • Spain
      • Alicante, Spain
      • Barcelona, Spain
      • Cordoba, Spain
      • Madrid, Spain
      • Sabadell, Spain
      • Santander, Spain
      • Valencia, Spain
      • Zaragoza, Spain
    • A Coruña
      • Santiago de Compostela, A Coruña, Spain
    • Asturias
      • Oviedo, Asturias, Spain
    • Madrid
      • Majadahonda, Madrid, Spain
    • Navarra
      • Pamplona, Navarra, Spain
  • Sweden
      • Gothenburg, Sweden
      • Stockholm, Sweden
  • Switzerland
      • Bern, Switzerland
      • Zurich, Switzerland
  • United States
    • Arizona
      • Tucson, Arizona, United States
    • California
      • Los Angeles, California, United States
      • Orange, California, United States
    • District of Columbia
      • Washington, District of Columbia, United States
    • Florida
      • Gainesville, Florida, United States
    • Illinois
      • Chicago, Illinois, United States
    • Kansas
      • Westwood, Kansas, United States
    • Louisiana
      • New Orleans, Louisiana, United States
    • Maine
      • Scarborough, Maine, United States
    • Massachusetts
      • Boston, Massachusetts, United States
    • Michigan
      • Detroit, Michigan, United States
    • Minnesota
      • Minneapolis, Minnesota, United States
    • New Jersey
      • Hackensack, New Jersey, United States
    • New York
      • New York, New York, United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States
    • South Carolina
      • Charleston, South Carolina, United States
    • Texas
      • Dallas, Texas, United States
      • Galveston, Texas, United States
      • Houston, Texas, United States
    • Washington
      • Seattle, Washington, United States

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically confirmed HCC that is inoperable (where surgery is not indicated due to disease extension, co-morbidities, or other technical reasons), and not eligible for local therapy
  • MET Diagnostic-High tissue reported by the central authorized laboratory using archival or recent biopsy tumor samples
  • Received at least 4 weeks of one prior sorafenib containing systemic therapy and then experienced documented radiographic disease progression; or inability to tolerate prior therapy received for at least a minimum period of time.
  • Discontinued prior systemic treatment or any investigational drug for at least 2 weeks (14 days) or for at least 3 weeks for IV anti-cancer drugs, prior to the study randomization
  • Local or loco-regional therapy (i.e., surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed >= 4 weeks prior to randomization
  • Measurable disease as defined by the RECIST v1.1.

Exclusion Criteria:

  • More than 1 prior systemic regimen (prior MET inhibitors/antibodies are not allowed; experimental systemic therapy for inoperable HCC given before or after sorafenib counts as separate regimen and is not allowed)
  • Child-Pugh B-C cirrhotic status based on clinical findings and laboratory results
  • Previous or concurrent cancer that is distinct from HCC in primary site or histology, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors. Any cancer curatively treated more than 3 years prior to enrollment is permitted.
  • History of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification within 6 months prior to study entry; active coronary artery disease (CAD); clinically significant bradycardia or other uncontrolled, cardiac arrhythmia defined as greater than or equal to Grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), or uncontrolled hypertension; myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring more than 6 months prior to study entry is permitted)
  • Active clinically serious infections defined as >= Grade 3 according to NCI CTCAE
  • Any medical, psychological, or social conditions, particularly if unstable, including substance abuse, that may, in the opinion of the Investigator, interfere with the subject's safety or participation in the study, protocol compliance, or evaluation of the study results
  • Known human immunodeficiency virus (HIV) infection
  • Blood or albumin transfusion within 5 days prior to the blood draw being used to confirm eligibility
  • Concomitant interferon therapy or therapies for active Hepatitis C virus (HCV) infection
  • Pregnancy or breast-feeding
  • History of liver transplant
  • Inability to swallow oral medications
  • Clinically significant gastrointestinal bleeding occurring <= 4 weeks prior to randomization
  • Pleural effusion or clinically evident (visible or palpable) ascites

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Tivantinib 240 mg BID Cohort
The tivantinib dosage of 240 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.
Drug: Tivantinib
Tivantinib tablets
Other Names:
  • ARQ197
Experimental: Tivantinib 120 mg BID Cohort
Tivantinib 120 mg is administered by oral tablet BID, once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).
Drug: Tivantinib
Tivantinib tablets
Other Names:
  • ARQ197
Placebo Comparator: Placebo Matching 240 mg BID Cohort
Matching placebo is administered by oral tablet(s) BID, once in the morning and once in the evening, with food.
Drug: Placebo
Matching placebo tablets
Other Names:
  • Placebo comparator
Placebo Comparator: Placebo Matching 120 mg BID Cohort
Matching placebo is administered by oral tablet(s) BID, once in the morning and once in the evening, with food.
Drug: Placebo
Matching placebo tablets
Other Names:
  • Placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Median Overall Survival (OS) Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy
Time Frame: within 36 months
Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort.
within 36 months
Overall Survival (OS) Rate At Different Time Points Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy
Time Frame: within 36 months
Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort.
within 36 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free Survival Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy (ITT Population)
Time Frame: within 10 months
Progression-free survival (PFS) is defined as the time from the date of randomization to the date of the first radiographic disease progression or death due to any cause. The rate of PFS (percentage of participants still alive without disease progression) was determined only in the tivantinib 120 mg BID cohort.
within 10 months
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy
Time Frame: Baseline to 30 days after last dose, up to approximately 4 years
Treatment-emergent adverse events (TEAEs) are reported for the tivantinib 120 mg BID cohort group.
Baseline to 30 days after last dose, up to approximately 4 years
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy
Time Frame: Baseline to 30 days after last dose, up to approximately 4 years
Treatment-emergent adverse events (TEAEs) are reported for the tivantinib 240 mg BID cohort group.
Baseline to 30 days after last dose, up to approximately 4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Daiichi Sankyo, Inc.

Collaborators

ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 27, 2012

Primary Completion (Actual)

March 28, 2017

Study Completion (Actual)

July 31, 2017

Study Registration Dates

First Submitted

December 19, 2012

First Submitted That Met QC Criteria

December 19, 2012

First Posted (Estimate)

December 24, 2012

Study Record Updates

Last Update Posted (Actual)

April 6, 2021

Last Update Submitted That Met QC Criteria

March 12, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ARQ197-A-U303
  • 2012-003308-10 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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